Diseases causing chronic inflammation or ulceration in the mucosal membrane of the large intestine and small intestine are collectively called inflammatory bowel disease. As the inflammatory bowel disease, ulcerative colitis and Crohn's disease are typically known, which are both intractable diseases. Ulcerative colitis is an inflammatory disease producing ulcer and erosion in the large-intestinal mucosa and exhibiting various systemic symptoms including hemorrhagic diarrhea, abdominal pain and fever. Crohn's disease is an inflammatory disease producing non-continuous ulcer and inflammation throughout the entire alimentary canal tract from the oral cavity to the anus and exhibiting systemic symptoms such as abdominal pain, fever, chronic diarrhea and malnutrition.
A sulfotransferase, more specifically, carbohydrate sulfotransferase 15 (CHST15) (also referred to as GalNAc4S-6ST or N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase), is a type II transmembrane Golgi protein, which transfers a sulfate to the 6-position of a GalNAc (4SO4) residue of chondroitin sulfate-A (CS-A) to synthesize highly sulfated chondroitin sulfate-E (CS-E). The present inventors have reported that submucosal administration of siRNA (CHST15 siRNA) which suppresses expression of CHST15 gene to the large-intestine of an animal model of a colitis, decreases expression of the CHST15 gene in the large intestine and produces therapeutic effects including suppression of ulceration, inflammation and fibrosis; and that the therapeutic effects were also exerted in human patients with Crohn's disease (Patent Literatures 1 to 3 and Non Patent Literatures 1 and 2). In addition, it has been recently reported that CHST15 siRNA locally administered has an effect on dilated cardiomyopathy and pancreatic cancer (Non Patent Literatures 3 to 6).
Since oligonucleotide therapeutics such as siRNA is easily degraded by an enzyme such as nuclease, siRNA is often topically administered to affected sites, for example, by injection or a special drug delivery system. However, the local administration is limited in the administration site and must be carried out by a doctor. Because of this, development of a preparation having a dosage form, that can be simply and less invasively administered to many sites, such as an oral preparation, has been desired.
Chitosan is a high molecular-weight polysaccharide, which can be produced by deacetylation of chitin, a main component of the shell of arthropods such as crustaceans and insects and the cell wall of fungi. Patent Literatures 4 and 5 disclose a composition for delivering siRNA, which contains chitosan and siRNA. However, Patent Literatures 4 and 5 do not disclose that chitosan is acetylated, and the obtained acetylated chitosan is used in combination with siRNA, at all. Non Patent Literature 7 reports that a complex containing an N-acetylated chitosan and plasmid DNA can be delivered to the intestine by oral administration. However, Non Patent Literature 7 does not describe a complex formed of an RNAi molecule such as siRNA in combination with an N-acetylated chitosan, at all.